FDA Approves Pembrolizumab Regimen for Frontline Use in Squamous NSCLC

The FDA has approved pembrolizumab (Keytruda) for first-line use in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane) for the treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC).

The phase III KEYNOTE-407 trial, on which the approval was based, showed that combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in patients with metastatic squamous NSCLC.

Progression-free survival (PFS) was also improved with the addition of pembrolizumab. The median PFS was 6.4 months (95% CI, 6.2-8.3) with the PD-1 inhibitor compared with 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001). While the PFS benefit was also observed across all PD-L1 expression levels, there was a correlation between an increase in PD-L1 level and a greater magnitude of benefit.

The objective response rate (ORR) in the pembrolizumab arm was 58%, compared with 35% in the control arm. The median duration of response was 7.2 months (range, 2.4 to 12.4+) versus 4.9 months (range, 2.0 to 12.4+) in the pembrolizumab versus placebo arms, respectively.

In the pembrolizumab cohort, 28.1% of patients had stable disease, 6.1% had progressive disease, and 2.2% of patients were not evaluable for response. The corresponding rates in the chemotherapy-alone group were 37.0%, 13.9%, and 2.5%, respectively.

“The results that support this approval from the KEYNOTE-407 trial demonstrate the potential of Keytruda in combination with chemotherapy in patients with squamous non-small cell lung cancer, regardless of PD-L1 expression,” Balazs Halmos, MD, director of the multidisciplinary thoracic oncology program at the Montefiore Einstein Center for Cancer Care and director of clinical cancer genomics at the Albert Einstein College of Medicine, said in a statement. “With this important approval, more patients will have the opportunity to benefit from immunotherapy.

Trial Design

In the phase III KEYNOTE-407 trial (NCT02775435), 559 treatment-naive patients with metastatic squamous NSCLC received carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks or weekly nab-paclitaxel (100 mg/m2), plus pembrolizumab (200 mg every 3 weeks) or placebo for 4 cycles (each 3 weeks), followed by single-agent pembrolizumab (200 mg every 3 weeks) or placebo for up to 31 cycles, for a potential total of 35 cycles.

After the initial 4 cycles, patients randomized to the placebo arm were allowed to cross over to receive pembrolizumab for the potential additional 31 cycles. The coprimary endpoints were OS and PFS. A key secondary endpoint for the study was ORR.

Two-hundred seventy-eight patients were treated in the pembrolizumab cohort and 281 patients received treatment in the chemotherapy-alone arm. In the pembrolizumab arm, 121 patients remained on treatment and 157 had discontinued. The primary reasons for discontinuing were progressive disease (n = 99) and adverse events (AEs; n = 48). In the chemotherapy-alone arm, 72 patients remained on treatment, with 208 having discontinued, primarily due to progression (n = 166) and AEs (n = 25).

Patient characteristics were well balanced at baseline between the 2 arms. In the pembrolizumab arm, the median age was 65.0 years (range, 29-87), 79.1% of patients were men, 73.7% had an ECOG performance status of 1, 7.2% had stable brain metastases, and 92.1% were current/former smokers. Additionally, 60.8% received paclitaxel as their taxane, 6.1% had prior thoracic radiation, and 1.8% had prior (neo)adjuvant therapy.

PD-L1 status was measured by tumor proportion score (TPS). In the pembrolizumab arm, 34.2%, 37.1% and 26.1% had a PD-L1 TPS status of <1%, 1%-49%, and ≥50%, respectively. The corresponding rates in the placebo arm were 35.2%, 37.0%, and 26.0%, respectively.

The HR for OS was 0.61, 0.57, and 0.64 favoring the pembrolizumab arm in the TPS <1%, <1%-49%, and ≥50% subgroups, respectively. Across the same 3 subgroups, the HR for PFS favoring the pembrolizumab arm was 0.68, 0.56, and 0.37, respectively.

The median treatment duration was 6.3 months in the pembrolizumab arm compared with 4.7 months in the placebo arm. Grade 3/5 all-causes AEs occurred in 69.8% versus 68.2% of the 2 arms, respectively. Treatment-related AEs (TRAEs) led to discontinuation in 23.4% of the experimental arm versus 11.8% of the control arm. Grade 3/5 immune-mediated AEs and infusion reactions occurred in 10.8% versus 3.2% of the 2 arms respectively. Overall, TRAEs led to death in 3.6% versus 2.1% of the 2 arms, respectively.

Pembrolizumab currently has 2 FDA approvals in the frontline NSCLC setting. In October 2016, the FDA approved single-agent pembrolizumab for the frontline treatment of patients with metastatic NSCLC whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations. In May 2017, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression.